脱水素クロスカップリング(CDC)で電子不足２重結合の両端をアシル化して目的物を合成しようとしました。
ジオキソランで保護したアルデヒドを使い，うまくいきそうでしたが，最後の脱保護ができず，断念。
そこで，まずアルデヒドの付加と酸化でCDCと同様の変換をおこない，次いで新たな条件化でのCDCを見つけてアシル化，全合成を完成しました。
新たなCDCの反応機構について，詳しく考察しています。tert-ブトキシラジカルができてHATで生じたアシルラジカルがマイケル付加するところから始まる４種類の経路を想定し，実験，計算でもっともらしい経路を特定しています。
They tried to synthesize the desired product by acylating both ends of an electron-deficient double bond by dehydrogenative cross-coupling (CDC).
Using dioxolane-protected aldehydes, it seemed to work, but the final deprotection was unfortunately unsuccessful.
So they first performed the same transformation as CDC by addition of the aldehyde followed by oxidation. Then they found CDC under new conditions and completed the total synthesis.
The reaction mechanism of the new CDC is discussed in detail. Four different pathways are postulated, starting with formation of the tert-butoxy radical, generation of the acyl radical by HAT, and Michael addition. The most plausible pathway is identified through some experiments and calculations.
In the synthesis of Alstoscholarinoid A, a 7-5 bicyclic system was constructed by an intramolecular aldol reaction of a 10-membered ring diketone, but the target product was obtained in low yield because the most sterically crowded hydrogen must be extracted. However, the Hock rearrangement of the hydroperoxide formed by singlet oxygen regioselectively produces the desired enolate with C-C bond cleavage, and the aldol reaction gives the desired product in a single step: cascade of Schenck ene reaction, Hock rearrangement, acetal cleavage, and aldol addition. It is not an unknown reaction, but an interesting one.
Alstocholarinoid B was obtained by an aldol reaction of dialdehyde. This reaction proceeded regioselectively without any problem.
As the same transformation reaction as Michael addition of enolate to α,β-unsaturated ketone (synthesis of 1,5-carbonyl compounds), they propose 2+2 cyclization ➞ oxidation ➞ retroaldol reaction with alkenylboronic acid esters and further upgrade it to an asymmetric reaction.
The Michael reaction takes a pyramidal transition state, which is thermodynamically and kinetically unfavorable for cyclic compounds that can only adopt a planar structure, but the photocyclization proceeds through biradical intermediates in the possibly favorable direction. (DF calculations available)
They exchange pinacol with chiral diols to make chiral boronic acid esters, and further synthesize esters where primary alcohols remain that improve ee by involving hydrogen bonds in the transition state.
In addition to synthesis of saxitoxin, they also performed 2+2 reactions with allyl alcohols to make chiral cyclobutanes, etc. Here, the hydrogen bond from the chiral auxiliary to the oxygen of the boronate formed from the alkoxide and the boron atom is an important factor for asymmetry induction.
The key transformation (formal [3+2] cyclization) is the 1,2 addition of a vinyl anion to an α,β-unsaturated ketone to give tert-divinyl carbinol (TDC), followed by treatment of the TDC with TEMPO-BF4 to give the Nazarov cyclization product cyclopentadiene (cyclopentenone if the oxidative pathway is possible).
Other typical C-C bond formation reactions such as asymmetric Claisen reaction, conjugate addition-aldol reaction, ring-closing metathesis, and aldol reaction are skillfully used to create the carbon skeleton.
The last step, aldol lactonization, can be stereoselective because one of the stereoisomers is captured by the lactonization.
The key step is the cascade reactions developed by the authors for the bislactone. Since there is a tetrasubstituted benzene ring in the middle of the molecule, the retrosynthesis was redesigned.
Two building blocks of similar size containing chiral centers were created, linked by cross-coupling, and the core skeleton was constructed by Friedel-Crafts.
Optimization of the F-C conditions was not easy because the benzene ring is not electron-rich.
When C6-C7 was a double bond, the yield after F-C could not be improved. Some compromises could not be avoided here and there.
Chiral centers are introduced by orthodox Sharpless dihydroxylation and CBS reduction. Chiral inductions are orthodox as well.
The way to construct the skeleton is tricky.
Mukaiyama➞ intramolecular Hosomi-Sakurai➞ 7-membered ring cyclization cascade starting from bridgehead carbocation➞ 1,2 transfer of alkyl groups to epoxy groups➞ radical cyclization starting from allyl iodide➞ radical alkyl [1,2] transfer.
What kind of precedents were referenced and what kind of considerations were made to lead to this pathway?
Furthermore, the ketone was stereoselectively reduced by the 1,4-shift of the hydride under the hydroxyl group As the author states in the summary, two “transformations involving C-H bonds” are artificially used in the synthesis of such complex natural products.
Particularly impressive is the reaction in which hydrogen is removed from an aliphatic (inert) C-H and, after rearrangement of the carbon skeleton, hydrogen is returned, with no change in molecular weight. (If you take hydrogen from everywhere, you just give hydrogen back if there is no next reaction. Is this called a “reversible C-H bond sampling strategy”?)
The target scaffold is constructed by cyclopropanation by generating a rhodium carbenoid from a triazole.
The isomerization by inversion of the tertiary amine nitrogen lone pair leads to a possible conformation for cyclopropanation. This condition is explained by the DFT calculation that the Boc protection of the indole nitrogen is crucial.
The rhodium carbenoid forms an aziridinium ylide intermediate, which is the precursor for cyclopropanation. The intermediate came out of the calculation, but it is a reasonable result since ylide and carbene are related.
It will be useful to remember that cyclopropanation competes with the 1,2-H shift.
The convergent construction of the carbon skeleton by the Mukaiyama-Michael reaction is wonderful, and you will learn a lot from the difficulties and chemical considerations that followed.
The need to protect the phenol arose. Since southeastern cyclohexene is not prone to aromatization, they came up with the idea of protecting it with an intramolecular ether through the SN2 reaction. This leads to the final reaction to form a nitrogen-containing six-membered ring.
There were many unfamiliar reactions, but the reaction mechanisms, such as Michael and vinylogous substitution reactions, were quite understandable.
The [5+2] addition of o-quinone is the key step.
The double Michael was assumed, but the reaction did not work with most catalysts, and good results were obtained with a mixed primary amine derived from a cinchona alkaloid. I did not understand the reaction mechanism well, but it seems to be a stepwise [5+2] addition reaction, not a double Michael. This was deduced from isotope effects and other factors.
The aromatic ring is formed by the DA-reteroDA cascade invented by Dr. Danishefsky.
The asymmetric quaternary center containing oxygen is constructed by asymmetric cyanosilylation. Amazing that it is already a practical level.
(−)-Elodeoidins A and B uploaded
https://www.ohira-sum.com/wp-content/uploads/2025/04/jacsau25-1096.pdf
脱水素クロスカップリング(CDC)で電子不足２重結合の両端をアシル化して目的物を合成しようとしました。
ジオキソランで保護したアルデヒドを使い，うまくいきそうでしたが，最後の脱保護ができず，断念。
そこで，まずアルデヒドの付加と酸化でCDCと同様の変換をおこない，次いで新たな条件化でのCDCを見つけてアシル化，全合成を完成しました。
新たなCDCの反応機構について，詳しく考察しています。tert-ブトキシラジカルができてHATで生じたアシルラジカルがマイケル付加するところから始まる４種類の経路を想定し，実験，計算でもっともらしい経路を特定しています。
They tried to synthesize the desired product by acylating both ends of an electron-deficient double bond by dehydrogenative cross-coupling (CDC).
Using dioxolane-protected aldehydes, it seemed to work, but the final deprotection was unfortunately unsuccessful.
So they first performed the same transformation as CDC by addition of the aldehyde followed by oxidation. Then they found CDC under new conditions and completed the total synthesis.
The reaction mechanism of the new CDC is discussed in detail. Four different pathways are postulated, starting with formation of the tert-butoxy radical, generation of the acyl radical by HAT, and Michael addition. The most plausible pathway is identified through some experiments and calculations.
Alstoscholarinoids A and B uploaded
https://www.ohira-sum.com/wp-content/uploads/2025/04/jacsau25-1076.pdf
Alstoscholarinoid Aの合成では，10員環ジケトンの分子内アルドールで7-5の２環系をつくりますが，目的物をつくるためには最も立体的に混み合った水素を引き抜かなければならないので，低収率でしか得られません。しかし一重項酸素でできるハイドロパーオキシドのHock転移で，C-C結合開裂と共に，位置選択的に目的のエノラートが発生し，アルドール反応で，目的物を一挙に得ることができました。Schenck Ene反応，Hock転移，アセタール開裂，アルドール付加のカスケード反応です。未知の反応では無いようですが，面白い反応です。
Alstocholarinoid Bの方はジアルデヒドのアルドール反応で，こちらは問題なく位置選択的に進んでいます。
In the synthesis of Alstoscholarinoid A, a 7-5 bicyclic system was constructed by an intramolecular aldol reaction of a 10-membered ring diketone, but the target product was obtained in low yield because the most sterically crowded hydrogen must be extracted. However, the Hock rearrangement of the hydroperoxide formed by singlet oxygen regioselectively produces the desired enolate with C-C bond cleavage, and the aldol reaction gives the desired product in a single step: cascade of Schenck ene reaction, Hock rearrangement, acetal cleavage, and aldol addition. It is not an unknown reaction, but an interesting one.
Alstocholarinoid B was obtained by an aldol reaction of dialdehyde. This reaction proceeded regioselectively without any problem.
(+)-Saxitoxin uploaded
https://www.ohira-sum.com/wp-content/uploads/2025/04/jacs25-9091.pdf
α,β-不飽和ケトンへのエノラートのマイケル付加と同じ変換反応（1,5-カルボニル化合物合成）として，アルケニルボロン酸エステルとの2+2環化➞酸化➞レトロアルドール反応を提案，さらに不斉反応にまでレベルアップさせてます。
マイケルだとピラミダルな遷移状態を取るので，平面構造しかとれないような環状化合物では，熱力学的にも速度論的にも不利な方向になるけど，光環化だとビララジカルになるので，可能な方向になる。（DF計算あり）
ピナコールとキラルジオールを交換させて，キラルボロン酸エステルをつくり，さらに一級アルコールが残るエステルを合成し，遷移状態に水素結合を関与させることにより，eeを上げています。
サキシトキシンとは別にアリルアルコールとの2+2反応を行ってキラルシクロブタンなどを作っていますが，ここではアルコキシドとホウ素で作るボロナートの酸素へのキラル補助剤からの水素結合が不斉誘起の重要なファクターになります。
As the same transformation reaction as Michael addition of enolate to α,β-unsaturated ketone (synthesis of 1,5-carbonyl compounds), they propose 2+2 cyclization ➞ oxidation ➞ retroaldol reaction with alkenylboronic acid esters and further upgrade it to an asymmetric reaction.
The Michael reaction takes a pyramidal transition state, which is thermodynamically and kinetically unfavorable for cyclic compounds that can only adopt a planar structure, but the photocyclization proceeds through biradical intermediates in the possibly favorable direction. (DF calculations available)
They exchange pinacol with chiral diols to make chiral boronic acid esters, and further synthesize esters where primary alcohols remain that improve ee by involving hydrogen bonds in the transition state.
In addition to synthesis of saxitoxin, they also performed 2+2 reactions with allyl alcohols to make chiral cyclobutanes, etc. Here, the hydrogen bond from the chiral auxiliary to the oxygen of the boronate formed from the alkoxide and the boron atom is an important factor for asymmetry induction.
Fortalpinoid Q uploaded
https://www.ohira-sum.com/wp-content/uploads/2025/04/jacs25-9079.pdf
α,β-不飽和ケトンにヴィニルアニオンを1,2付加させてtert-ジビニルカルビノール(TDC)を作り，TEMPO-BF4で処理するとNazarov環化でシクロペンタジエン（oxidative Nazarovが起きればシクロペンテノン）ができる変換反応（結果的に[3+2]環化）が鍵段階。
その他クライゼン転移，共役付加-アルドール，閉環メタセシス，アルドールなど典型的炭素結合反応で炭素骨格をうまく作っています。
最後のアルドールラクトン化は一方の立体異性体のみがラクトン化することにおよって選択性が出たのでしょうか。
The key transformation (formal [3+2] cyclization) is the 1,2 addition of a vinyl anion to an α,β-unsaturated ketone to give tert-divinyl carbinol (TDC), followed by treatment of the TDC with TEMPO-BF4 to give the Nazarov cyclization product cyclopentadiene (cyclopentenone if the oxidative pathway is possible).
Other typical C-C bond formation reactions such as asymmetric Claisen reaction, conjugate addition-aldol reaction, ring-closing metathesis, and aldol reaction are skillfully used to create the carbon skeleton.
The last step, aldol lactonization, can be stereoselective because one of the stereoisomers is captured by the lactonization.
(-)-Rubriflordilactone B uploaded
https://www.ohira-sum.com/wp-content/uploads/2025/04/jacs25-7875.pdf
筆者らが開発したビスラクトンの合成法が鍵段階になりますが，まん中に四置換ベンゼン環があるので，全体の骨格合成は新たに考案しています。
不斉中心を含む同じくらいの大きさの２つのビルディングブロックをつくり，クロスカップリングで結び，Friedel-Craftsでコアの骨格を合成しました。
電子リッチでないベンゼン環なのでFriedel-Craftsの条件が難しかった。
C6-C7が二重結合だとF-Cの後の収率が上がらない。あちこちで妥協を避けられませんでした。
不斉はオーソドックスなSharplessジヒドロキシル化とCBS還元で導入。不斉誘導もオーソドックスです。
The key step is the cascade reactions developed by the authors for the bislactone. Since there is a tetrasubstituted benzene ring in the middle of the molecule, the retrosynthesis was redesigned.
Two building blocks of similar size containing chiral centers were created, linked by cross-coupling, and the core skeleton was constructed by Friedel-Crafts.
Optimization of the F-C conditions was not easy because the benzene ring is not electron-rich.
When C6-C7 was a double bond, the yield after F-C could not be improved. Some compromises could not be avoided here and there.
Chiral centers are introduced by orthodox Sharpless dihydroxylation and CBS reduction. Chiral inductions are orthodox as well.
uploaded (+)-Kobusine, (+)-Spirasine IX , (+)-Orgetine
https://www.ohira-sum.com/wp-content/uploads/2025/04/jacs25-8132.pdf
骨格の作り方がトリッキーです。
向山➞分子内細見-櫻井➞橋頭位カルボカチオンから始まる７員環化カスケード➞エポキシ基へのアルキル基の1,2移動➞ヨウ化アリルから始まるラジカル環化➞ラジカル[1,2]移動。
いったい，どのような先例反応を参考にし，どのような思考過程でこのような経路に至ったのでしょう。
更に，水酸基の付け根のハイドライドの1,4シフトでケトンを立体選択的に還元しています。
まとめで作者が述べているうように，２つの“transformation involving C-H bond”がこのような複雑な天然物合成に計画的に使われています。
特にアリファティックな（不活性な）C-Hから水素を引き抜き，炭素骨格の転位の後，水素を返して，前後で分子量の変化なしという反応（1,4-H shiftもそうですが）が斬新です。（あちこちから水素を引き抜いても次の反応がなければ水素を返すだけ。”reversible C-H bond sampling strategy”というのでしょうか？）
The way to construct the skeleton is tricky.
Mukaiyama➞ intramolecular Hosomi-Sakurai➞ 7-membered ring cyclization cascade starting from bridgehead carbocation➞ 1,2 transfer of alkyl groups to epoxy groups➞ radical cyclization starting from allyl iodide➞ radical alkyl [1,2] transfer.
What kind of precedents were referenced and what kind of considerations were made to lead to this pathway?
Furthermore, the ketone was stereoselectively reduced by the 1,4-shift of the hydride under the hydroxyl group As the author states in the summary, two “transformations involving C-H bonds” are artificially used in the synthesis of such complex natural products.
Particularly impressive is the reaction in which hydrogen is removed from an aliphatic (inert) C-H and, after rearrangement of the carbon skeleton, hydrogen is returned, with no change in molecular weight. (If you take hydrogen from everywhere, you just give hydrogen back if there is no next reaction. Is this called a “reversible C-H bond sampling strategy”?)
(-)-Rauvomine B uploaded
https://www.ohira-sum.com/wp-content/uploads/2025/04/jacs24-22047.pdf
トリアゾールからロジウムカルベノイドを発生させてシクロプロパン化で目的骨格を構築します。
３級アミン窒素ローンペアの反転による異性化でシクロプロパン化の可能なコンフォーメーションになるのですが，その条件がインドール窒素のBoc保護ということで，DFT計算で説明してます。
ロジウムカルベノイドからアジリジウムイリド中間体ができそれがシクロプロパン化の前駆体となります。計算でその中間体が出てきたらしいですが，イリドとカルベンは親戚なのでごもっともな結果です。
シクロプロパン化と1,2-H shiftが競合するというのは覚えておきたい一般的知見です。
The target scaffold is constructed by cyclopropanation by generating a rhodium carbenoid from a triazole.
The isomerization by inversion of the tertiary amine nitrogen lone pair leads to a possible conformation for cyclopropanation. This condition is explained by the DFT calculation that the Boc protection of the indole nitrogen is crucial.
The rhodium carbenoid forms an aziridinium ylide intermediate, which is the precursor for cyclopropanation. The intermediate came out of the calculation, but it is a reasonable result since ylide and carbene are related.
It will be useful to remember that cyclopropanation competes with the 1,2-H shift.
Aleutianamine uploaded
https://www.ohira-sum.com/wp-content/uploads/2025/03/jacs25-5736.pdf
向山ーマイケルで炭素骨格を収束的につくるところもすばらしいですが，その後の苦労話ー化学的考察などが，いろいろ勉強になります。
フェノールを保護する必要が生じ，southeastのシクロヘキセンが，芳香化しにくいことから，SN2反応させて分子内エーテルで保護することを思いつきます。それが最後の含窒素6員環をつくる反応に繋がります。
馴染の少ない反応が多くありましたが，Michaelやvinylogousな置換反応など，反応機構はごもっともなものでした。
The convergent construction of the carbon skeleton by the Mukaiyama-Michael reaction is wonderful, and you will learn a lot from the difficulties and chemical considerations that followed.
The need to protect the phenol arose. Since southeastern cyclohexene is not prone to aromatization, they came up with the idea of protecting it with an intramolecular ether through the SN2 reaction. This leads to the final reaction to form a nitrogen-containing six-membered ring.
There were many unfamiliar reactions, but the reaction mechanisms, such as Michael and vinylogous substitution reactions, were quite understandable.
uploaded Asperones A and B
https://www.ohira-sum.com/wp-content/uploads/2025/03/jacs25-6739.pdf
o-キノンの[5+2]付加がキーステップとなります。
ダブルマイケルを想定していましたがほとんどの触媒でうまくいかず，結局シンコナアルカロイド由来の混み合った一級アミンで好結果が得られました。反応機構については，私はよく理解できなかったのですが，ダブルマイケルではなく，stepwiseな[5+2]付加反応らしい。同位体効果などから結論づけてます。
芳香環はDA−reteroDAカスケードで作っています。ダニシェフスキー先生考案の反応とのこと。
酸素を含む不斉４級中心は不斉シアノシリル化。実用レベルまで来てるんですね。
The [5+2] addition of o-quinone is the key step.
The double Michael was assumed, but the reaction did not work with most catalysts, and good results were obtained with a mixed primary amine derived from a cinchona alkaloid. I did not understand the reaction mechanism well, but it seems to be a stepwise [5+2] addition reaction, not a double Michael. This was deduced from isotope effects and other factors.
The aromatic ring is formed by the DA-reteroDA cascade invented by Dr. Danishefsky.
The asymmetric quaternary center containing oxygen is constructed by asymmetric cyanosilylation. Amazing that it is already a practical level.